NM_019098.5:c.1208G>A

Variant names:

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM1BS1_SupportingBS2

The NM_019098.5(CNGB3):c.1208G>A(p.Arg403Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00313 in 1,612,558 control chromosomes in the GnomAD database, including 73 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0022 ( 5 hom., cov: 32)

Exomes 𝑓: 0.0032 ( 68 hom. )

Consequence

CNGB3
NM_019098.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:4U:4B:8

Conservation

PhyloP100: 2.14

Variant links:

Genes affected

CNGB3 (HGNC:2153): (cyclic nucleotide gated channel subunit beta 3) This gene encodes the beta subunit of a cyclic nucleotide-gated ion channel. The encoded beta subunit appears to play a role in modulation of channel function in cone photoreceptors. This heterotetrameric channel is necessary for sensory transduction, and mutations in this gene have been associated with achromatopsia 3, progressive cone dystrophy, and juvenile macular degeneration, also known as Stargardt Disease. [provided by RefSeq, Feb 2010]

CNGB3 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -3 ACMG points.

PM1

In a topological_domain Cytoplasmic (size 36) in uniprot entity CNGB3_HUMAN there are 5 pathogenic changes around while only 0 benign (100%) in NM_019098.5

BS1

Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00217 (330/152224) while in subpopulation SAS AF= 0.0307 (148/4820). AF 95% confidence interval is 0.0267. There are 5 homozygotes in gnomad4. There are 184 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

BS2

High Homozygotes in GnomAd4 at 5 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CNGB3	NM_019098.5 link	c.1208G>A	p.Arg403Gln	missense_variant	Exon 11 of 18	ENST00000320005.6	NP_061971.3	Q9NQW8-1
CNGB3	XM_011517138.3 link	c.794G>A	p.Arg265Gln	missense_variant	Exon 9 of 16		XP_011515440.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
CNGB3	ENST00000320005.6 link	c.1208G>A	p.Arg403Gln	missense_variant	Exon 11 of 18	1	NM_019098.5	ENSP00000316605.5	Q9NQW8-1
CNGB3	ENST00000681546.1 link	n.1028G>A		non_coding_transcript_exon_variant	Exon 6 of 13
CNGB3	ENST00000681746.1 link	n.1208G>A		non_coding_transcript_exon_variant	Exon 11 of 19			ENSP00000505959.1	A0A5J6DSN8

Frequencies

GnomAD3 genomes

AF:

0.00219

AC:

333

AN:

152106

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000483

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000721

Gnomad ASJ

AF:

0.00288

Gnomad EAS

AF:

0.00347

Gnomad SAS

AF:

0.0313

Gnomad FIN

AF:

0.000378

Gnomad MID

AF:

0.0285

Gnomad NFE

AF:

0.00157

Gnomad OTH

AF:

0.00143

GnomAD3 exomes

AF:

0.00458

AC:

1150

AN:

251014

Hom.:

AF XY:

0.00598

AC XY:

812

AN XY:

135674

show subpopulations

Gnomad AFR exome

AF:

0.000431

Gnomad AMR exome

AF:

0.000580

Gnomad ASJ exome

AF:

0.00308

Gnomad EAS exome

AF:

0.00158

Gnomad SAS exome

AF:

0.0273

Gnomad FIN exome

AF:

0.000185

Gnomad NFE exome

AF:

0.00182

Gnomad OTH exome

AF:

0.00262

GnomAD4 exome

AF:

0.00323

AC:

4711

AN:

1460334

Hom.:

Cov.:

AF XY:

0.00410

AC XY:

2981

AN XY:

726498

show subpopulations

Gnomad4 AFR exome

AF:

0.000150

Gnomad4 AMR exome

AF:

0.000582

Gnomad4 ASJ exome

AF:

0.00249

Gnomad4 EAS exome

AF:

0.00497

Gnomad4 SAS exome

AF:

0.0282

Gnomad4 FIN exome

AF:

0.000225

Gnomad4 NFE exome

AF:

0.00153

Gnomad4 OTH exome

AF:

0.00372

GnomAD4 genome

AF:

0.00217

AC:

330

AN:

152224

Hom.:

Cov.:

AF XY:

0.00247

AC XY:

184

AN XY:

74424

show subpopulations

Gnomad4 AFR

AF:

0.000481

Gnomad4 AMR

AF:

0.000720

Gnomad4 ASJ

AF:

0.00288

Gnomad4 EAS

AF:

0.00348

Gnomad4 SAS

AF:

0.0307

Gnomad4 FIN

AF:

0.000378

Gnomad4 NFE

AF:

0.00157

Gnomad4 OTH

AF:

0.00142

Alfa

AF:

0.00181

Hom.:

Bravo

AF:

0.00141

TwinsUK

AF:

0.00297

AC:

ALSPAC

AF:

0.00285

AC:

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.00198

AC:

ExAC

AF:

0.00509

AC:

618

Asia WGS

AF:

0.0120

AC:

AN:

3470

EpiCase

AF:

0.00278

EpiControl

AF:

0.00219

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:4Uncertain:4Benign:8

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Benign:4

Nov 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

CNGB3: BS1, BS2 -

May 27, 2022

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

See Variant Classification Assertion Criteria. -

Jan 23, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Department of Ophthalmology and Visual Sciences Kyoto University

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Achromatopsia

Pathogenic:2Uncertain:1

Mar 20, 2018

Molecular Genetics Laboratory, Institute for Ophthalmic Research

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

- -

Jan 08, 2020

Natera, Inc.

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jun 23, 2019

Sharon lab, Hadassah-Hebrew University Medical Center

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: research

- -

Achromatopsia 3

Pathogenic:1Benign:1

Mar 27, 2017

Molecular Genetics Laboratory, Institute for Ophthalmic Research

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: research

- -

May 18, 2021

Genome-Nilou Lab

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified

Uncertain:1Benign:1

Apr 22, 2015

Eurofins Ntd Llc (ga)

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Aug 01, 2024

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: CNGB3 c.1208G>A (p.Arg403Gln) results in a conservative amino acid change located in the ion transport domain (IPR005821) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0046 in 251014 control chromosomes, predominantly at a frequency of 0.027 within the South Asian subpopulation in the gnomAD database, including 24 homozygotes. The observed variant frequency within South Asian control individuals in the gnomAD database is approximately 5-fold of the estimated maximal expected allele frequency for a pathogenic variant in CNGB3 causing Achromatopsia (0.005), strongly suggesting that the variant is a benign polymorphism found primarily in populations of South Asian origin. Biallelic mutations in CNBG3 cause autosomal recessive Achromatopsia. However, the c.1208G>A variant has been reported in patients who present with a highly variable range of clinical findings from mild macular dystrophy to severe cone dystrophy with near complete loss of cone function (eg. Michaelides_2004, Lin_2017, Greenberg_2014, Jinda_2021, Burkard_2018, Mayer_2017). One in depth exploration of a large cohort of patients with the variant suggests the variant is a hypomorphic mutation that may cause relatively mild and late-onset or subclinical retinal disease in the homozygous state and may be a cause of digenic triallelic disease due to the correlation of disease severity with CNGB3 and CNGA3 genoytpes (Burkard_2018). Consistent with the clinical findings, a Cngb3-R403Q/R403Q mouse model, which was crossbred with Cnga3-deficient (Cnga3/) mice to obtain triallelic Cnga3+/ Cngb3R403Q/R403Q mutants showed striking genotype-phenotype correlation, since the presence of 1 Cnga3-null allele exacerbated the cone dystrophy phenotype in Cngb3R403Q/R403Q mice (Burkard_2018). A different functional study found that co-expression of WT CNGA3 and mutant CNGB3/p.R403Q in Xenopus oocytes resulted in formation of heterotetrameric CNG channels with normal surface expression, but increased apparent ligand sensitivity and increased outward rectification, suggesting a gain-of-function mechanism (Bright_2005). The following publications have been ascertained in the context of this evaluation (PMID: 16379026, 30418171, 24504161, 32869108, 28418496, 28795510, 15161866, 37734845). ClinVar contains an entry for this variant (Variation ID: 143154). Based on the evidence outlined above, the variant was classified as uncertain significance. -

Severe early-childhood-onset retinal dystrophy

Benign:2

Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: research

The p.Arg403Gln variant in CNGB3 has been identified in 3 homozygous Pakistani individuals with progressive cone dystrophy, 1 homozygous Pakistani individual with complete achromatopsia, and in the heterozygous state in 1 individual with progressive cone dystrophy, segregated with eye disease in 4 relatives from 1 family (PMID: 15161866, 24504161), and has been identified in >2% of South Asian chromosomes and 13 homozygotes by ExAC (http://gnomad.broadinstitute.org/). In vitro functional studies provide some evidence that the p.Arg403Gln variant may slightly impact protein function (PMID: 16379026). However, these types of assays may not accurately represent biological function. In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely benign for autosomal recessive progressive cone dystrophy. -

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Abnormality of the eye

Pathogenic:1

Jun 18, 2017

Genomic Research Center, Shahid Beheshti University of Medical Sciences

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Retinal dystrophy

Uncertain:1

Jan 01, 2023

Institute of Human Genetics, Univ. Regensburg, Univ. Regensburg

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Retinitis pigmentosa

Uncertain:1

Sep 01, 2016

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.45

BayesDel_addAF

Benign

-0.031

BayesDel_noAF

Pathogenic

0.20

CADD

Uncertain

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.59

Eigen

Uncertain

0.51

Eigen_PC

Uncertain

0.52

FATHMM_MKL

Uncertain

0.88

LIST_S2

Uncertain

0.94

MetaRNN

Benign

0.015

MetaSVM

Pathogenic

0.95

MutationAssessor

Uncertain

2.5

PrimateAI

Uncertain

0.51

PROVEAN

Benign

-2.2

REVEL

Pathogenic

0.71

Sift

Uncertain

0.021

Sift4G

Uncertain

0.041

Polyphen

0.97

Vest4

0.90

MVP

0.97

MPC

0.19

ClinPred

0.035

GERP RS

5.1

Varity_R

0.45

gMVP

0.92

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.27

Details are displayed if max score is > 0.2

DS_AL_spliceai

0.27

Position offset: 29

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over